Despite recent progress in anti-HIV therapy, drug toxicity and emergence of drug-resistant isolates during long- term treatment of HIV-infected patients necessitate the search for new targets that can be used to develop novel anti-viral agents. One such target is the viral cholesterol. A number of reports demonstrated that HIV infectivity critically depends on the amount of cholesterol incorporated into the viral particle during assembly. Our published studies showed that HIV-1 negatively affects reverse cholesterol transport (RCT), suggesting that the virus actively regulates cellular cholesterol metabolism. Our preliminary experiments revealed an unexpected phenomenon: stimulation of cholesterol efflux, the cellular component of RCT, potently inhibited HIV-1 replication. In this application, we propose to investigate the mechanism of anti-HIV activity of TO- 901317, a synthetic agonist of liver X receptor (LXR), which is a potent inducer of RCT. The following Specific Aims will be addressed: Specific Aim 1. To determine the mechanism of anti-HIV activity of the LXR agonist TO-901317. Specific Aim 2. To test the anti-HIV activity of TO-901317 in an in vivo model of HIV infection, humanized Rag-/-3c-/- mice. The rationale for the proposed research is that if the mechanism of anti-HIV activity of LXR agonists is understood and therapeutic potential of these compounds is demonstrated in an in vivo model of HIV infection, a program to develop these compounds for clinical use as anti-HIV agents can be initiated. Such compounds may be highly beneficial for HIV-infected patients. Indeed, they will not only target HIV replication, presumably by a novel mechanism, but, due to their stimulatory effect on RCT, will also help prevent development of atherosclerosis in HIV-infected patients. In addition, since these compounds target a cellular mechanism and not a viral enzyme, development of resistance to these drugs may be delayed or prevented. This exploratory proposal is fully consistent with the goals of this PA as it addresses an innovative concept in HIV research which has implications both for basic and translational studies. Upon completion, these studies are expected to define potent anti-HIV compounds working through a novel mechanism different from that of any other currently used drug. PUBLIC HEALTH RELEVANCE: Targeting HIV infectivity by stimulating cholesterol efflux The proposed research is highly relevant to public health, as it will investigate a new class of anti-HIV agents. These agents target HIV infectivity by a mechanism different from that of other anti-HIV drugs, and thus would be a useful addition to a drug combination used for highly active anti-retroviral therapy.